Lowering Albuminuria—Does It Lower the Cardiovascular Risk?
Authors: Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, Dahlo[Combining Diaeresis]f B, Devereux RB, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wan Y
Journal: Journal of the American Society of Nephrology (2005)

Recently, a great number of studies have provided solid support for the concept that microalbuminuria, originally described in diabetics (1–3) as a predictor of renal and cardiovascular risk, is a strong predictor of cardiovascular and renal risk in nondiabetic patients as well (4–8). The Prevention of Renal and Vascular Endstage Disease (PREVEND) study showed that in the general population diabetes mellitus or hypertension as potential causal factors do not account for microalbuminuria in the majority of individuals (9). It has also been shown that microalbuminuria is a potent predictor of cardiovascular events and cardiovascular death in prospective studies (4–6,10). It has even been argued whether microalbuminuria, as defined by past studies in diabetic patients (11), is optimal for risk prediction. Both in diabetic (12) and nondiabetic patients (13,14), urine albumin concentrations in the high normal range are significant predictors of cardiovascular risk. Following the hypothesis that proteinuria is a progression promoter (15,16), originally proposed by Remuzzi, convincing evidence has meanwhile been provided (17,18) that lowering of proteinuria is associated with less progression of renal disease. Consequently, proteinuria is today considered a valid target for renoprotective treatment in patients with manifest nephropathy. Beyond this, somewhat unexpectedly, reduction of proteinuria was also associated with a reduction of cardiovascular events in proteinuric patients with advanced diabetic nephropathy (19). So far it had not been known, however, whether this relation between regression of proteinuria and reduction of cardiovascular risk extends into the range of albumin excretion seen in microalbuminuric patients. The study by Asselbergs et al. (20) had shown that in microalbuminuric patients intervention with an angiotensin-converting enzyme inhibitor lowered the frequency of cardiovascular events. The recent Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study had shown a five-fold increase of cardiovascular events from the lowest to the highest decile of albumin excretion (14). The above study of Ibsen et al. now provides a further post hoc analysis of the LIFE study, which was designed to compare the effects of the angiotensin receptor blocker losartan and the β-blocker atenolol in patients with left ventricular hypertrophy (21). The analysis of Ibsen et al. yielded the remarkable result that the response of the albumin excretion rate to antihypertensive treatment predicts the frequency of future cardiovascular events. The urinary albumin/creatinine ratio was measured at baseline and annually thereafter. The change of albuminuria with time was closely related to the risk of the primary composite endpoint, i.e., the first occurrence of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death. The population was divided according to median baseline urinary albumin/creatinine ratio (1.21 mg/mmol) and 1-yr urinary albumin/creatinine ratio (0.67 mg/mmol). The risk of the occurrence of a primary endpoint was lowest in those individuals in whom the value was low, i.e., below the median, at baseline and remained low at 1 yr (frequency, 5.5%). The risk was higher in those with a low ratio at baseline but a high ratio at 1 yr (8.6%), and higher still in those with a low baseline but high 1-yr ratio (9.4%). The highest risk was found in those individuals who had a high ratio both at baseline and at yr 1 (13.5%). Interestingly, baseline and in-treatment systolic pressure as well as the choice of the antihypertensive agent, i.e., losartan or atenolol, explained only a small proportion of the risk modification. The consistency of the finding in this large population (n = 8206) is underlined by the fact that this relationship also was seen for the individual components of the primary endpoint, i.e., cardiovascular death, stroke, and myocardial infarction. Obviously one cannot draw conclusions with respect to causality from such associations, particularly in a post hoc analysis. Nevertheless, one can firmly state that a very tight relationship exists between change in albuminuria and cardiovascular risk, albuminuria thus providing useful clinical information. Both in diabetic (22) and in nondiabetic patients (23), microalbuminuria has been shown to be associated with generalized vascular leakiness for albumin and evidence of endothelial cell dysfunction and microinlammation (24), so microalbuminuria and presumably also high normal albuminuria can be considered as an index of microcirculatory disturbances. The nature of the link between the two abnormalities, i.e., albumin leak in the glomerulus and endothelial cell dysfunction, remains moot. Is it a podocyte problem? A hint in this direction could be the observation of Pereira et al. (25) that the risk of microalbuminuria is higher for individuals with a polymorphism of the podocin gene. How does this tie in with the evidence of an endothelial cell dysfunction? This is difficult to explain, but a pointer may be the observation that intense cross-talk exists between podocytes (as specialized pericytes) and (at least glomerular) endothelial cells (26,27). One can certainly conclude that it makes a lot of sense to monitor albumin excretion in high-risk patients at baseline and under antihypertensive treatment as proposed by the authors (28). Treatment should be adjusted or modified, including management of modifiable risk factors such as smoking, obesity, and dyslipidemia, if albumin excretion rates are not lowered appropriately by antihypertensive intervention. This study is one further piece of evidence which identifies albuminuria as a therapeutic goal. This conclusion is in line with recent efforts of our societies to heighten awareness of this novel risk factor in the medical community (29).